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The Journal of Neuroscience, July 16, 2003, 23(15):6385-6391
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Clozapine Reverses Hyperthermia and Sympathetically Mediated Cutaneous Vasoconstriction Induced by 3,4-Methylenedioxymethamphetamine (Ecstasy) in Rabbits and Rats
W. W. Blessing, B. Seaman, N. P. Pedersen, andY. Ootsuka Centre for Neuroscience, Departments of Medicine and Physiology, Flinders University, Bedford Park, South Australia 5042, Australia
Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1–5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 ± 0.5°C in 5 mg/kg clozapine-treated rabbits and 39.0 ± 0.2°C in olanzapine-treated rabbits, less than untreated animals (41.5 ± 0.3°C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 ± 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 ± 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 ± 0.5°C, <38.6 ± 0.3°C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 ± 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 ± 1 cm/sec) and the pre-MDMA level (17 ± 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.
Key words: cutaneous blood flow; cutaneous sympathetic nerve activity; serotonin; 5-HT1A receptors; 5-HT2A receptors; hallucinations; hyperthermia; body temperature; olanzapine; atypical antipsychotic agents
Received Jan. 2, 2003; revised May. 6, 2003; accepted May. 7, 2003.
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